# Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity

> **NIH NIH U01** · DANA-FARBER CANCER INST · 2024 · $985,172

## Abstract

Abstract
Unlike many cancers, pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic, nutrient-
deprived, immunosuppressive tumor microenvironment (TME) and a fibrotic stroma that may impair treatment
response. Recent single-cell studies suggest a complex interplay between malignant tumor cells and other cell
types within the TME, with crosstalk between tumor and stromal cell types influencing malignant cell phenotypes,
including responses to therapy. Understanding these interactions will provide insight into PDAC progression and
therapy resistance.
In particular, cancer-associated fibroblasts (CAFs) are a major non-immune cell component of the TME and are
comprised of several distinct subtypes that vary based on tumor subtype and the surrounding
microenvironmental niche. In this proposal, we bring together a multidisciplinary team of basic and translational
investigators that will build upon our prior studies to investigate the Tumor-TME co-organizer model with a focus
on interrogating interactions between PDAC tumor cells and CAFs in the TME. Specifically, we will examine the
overarching hypothesis that reciprocal signaling between tumor cells and CAFs shapes malignant cell and CAF
phenotypes in a context-specific manner that can be modulated by prior therapy and the organ-specific niche.
We will leverage multiple built-in capabilities, including genetically engineered mouse models (GEMMs), patient-
derived organoid (PDO) and matched fibroblast models, functional genetic screens and clinical trials with serial
biopsies to study the PDAC TME continuum in disease progression and resistance to therapy. Specifically, we
propose (1) to determine whether targeting organ-specific PDAC-CAF interactions enhances therapeutic
responses, (2) to interrogate novel vulnerabilities resulting from tumor cell and CAF reprogramming during PDAC
therapy, and (3) investigate whether TGFB blockade disrupts tumor cell-CAF crosstalk and sensitizes PDAC to
chemotherapy. In pursuing these studies, we will work with other members of the PDAC Stromal Reprogramming
Consortium (PSRC) to pursue collaborative studies to understand how PDAC and TME interactions program
tumor progression and therapy responses.

## Key facts

- **NIH application ID:** 10918120
- **Project number:** 5U01CA274276-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Andrew James Aguirre
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $985,172
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918120

## Citation

> US National Institutes of Health, RePORTER application 10918120, Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity (5U01CA274276-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10918120. Licensed CC0.

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